New drugs for hepatitis C virus

Pockros, Paul J.

doi:10.1586/17474124.1.1.145

Cited by 5 publications

(5 citation statements)

References 34 publications

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“…Nucleotides generated from nucleoside analogs can lead to premature termination and/or errors in the viral RNA. Although several inhibitors of HCV NS5B have progressed into clinical trials, severe side effects have resulted in the discontinuation of most drug candidates [7], [8], [9]. There is a significant need to develop better drugs specific for the HCV polymerase, especially for use in combination with other therapies.…”

Section: Introductionmentioning

confidence: 99%

A Cell-Based Assay for RNA Synthesis by the HCV Polymerase Reveals New Insights on Mechanism of Polymerase Inhibitors and Modulation by NS5A

et al. 2011

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RNA synthesis by the genotype 1b hepatitis C virus (HCV) polymerase (NS5B) transiently expressed in Human embryonic kidney 293T cells or liver hepatocytes was found to robustly stimulate RIG-I-dependent luciferase production from the interferon β promoter in the absence of exogenously provided ligand. This cell-based assay, henceforth named the 5BR assay, could be used to examine HCV polymerase activity in the absence of other HCV proteins. Mutations that decreased de novo initiated RNA synthesis in biochemical assays decreased activation of RIG-I signaling. In addition, NS5B that lacks the C-terminal transmembrane helix but remains competent for RNA synthesis could activate RIG-I signaling. The addition of cyclosporine A to the cells reduced luciferase levels without affecting agonist-induced RIG-I signaling. Furthermore, non-nucleoside inhibitor benzothiadiazines (BTDs) that bind within the template channel of the 1b NS5B were found to inhibit the readout from the 5BR assay. Mutation M414T in NS5B that rendered the HCV replicon resistant to BTD was also resistant to BTDs in the 5BR assay. Co-expression of the HCV NS5A protein along with NS5B and RIG-I was found to inhibit the readout from the 5BR assay. The inhibition by NS5A was decreased with the removal of the transmembrane helix in NS5B. Lastly, NS5B from all six major HCV genotypes showed robust activation of RIG-I in the 5BR assay. In summary, the 5BR assay could be used to validate inhibitors of the HCV polymerase as well as to elucidate requirements for HCV-dependent RNA synthesis.

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Section: Introductionmentioning

confidence: 99%

A Cell-Based Assay for RNA Synthesis by the HCV Polymerase Reveals New Insights on Mechanism of Polymerase Inhibitors and Modulation by NS5A

et al. 2011

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“…However, the occurrence of severe unwanted side effects has resulted in the discontinuation of their development. NM-283, the 3′-valine ester prodrug of 1 , was halted because of severe GI tract toxicity and hematological disorders, , while R-1626, the 2,3,5-triisobutyryl ester prodrug of 3 , was stopped mainly because of excessive neutropenia observed in some patients . Consequently, there is still a need for safe and well tolerated derivatives of this class of compounds.…”

Section: Introductionmentioning

confidence: 99%

2′-Deoxy-2′-spirocyclopropylcytidine Revisited: A New and Selective Inhibitor of the Hepatitis C Virus NS5B Polymerase

et al. 2010

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The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC(50) of 7.3 μM measured in the Huh7-Rep cell line and no associated cytotoxicity (CC(50) > 98.4 μM). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated. The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.

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“…We selected eligible studies by searching the PubMed and EMBASE electronic databases using pre‐determined search engines (Table S1) from 1 January 2007 to 17 April 2021. Although the DAA era began in 2013, 9 we opted to begin our search in 2007 as this marked the date that DAA therapies were first mentioned in the literature 11 . Our primary goal was to assess the outcomes of HCV seronegative recipients who received HCV viraemic solid allografts.…”

Section: Methodsmentioning

confidence: 99%

Systematic review: hepatitis C viraemic allografts to hepatitis C‐negative recipients in solid organ transplantation

Raasikh

Jamali

Flores

et al. 2021

Aliment Pharmacol Ther

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Summary Background Given the success of direct‐acting antivirals (DAAs) in treating hepatitis C (HCV), interest is growing in utilizing solid organs from allografts with active HCV to expand donor availability. Aim To review post‐transplant outcomes and patient survival in HCV‐negative recipients receiving solid organ transplants (SOT) from viraemic, that is, HCV+/NAT+ (nucleic acid testing) allografts. Methods A literature search was conducted on PubMed and EMBASE from 01/01/2007 to 4/17/2021 for articles matching eligibility criteria. Two authors independently screened titles and abstracts. Disagreements were solved by a third independent reviewer. Methodological quality assessment was done using a modified Newcastle‐Ottawa scale (NOS). Data synthesis was done qualitatively using median, ranges and percentages. Results Thirty‐five studies were included (or 852 SOTs): 343 kidney, 233 heart, 204 liver, and 72 lung transplants from viraemic allografts. Of the recipients eligible for sustained virological response at 12 weeks (SVR12) calculation, 100% achieved cure from HCV. No deaths/graft failures were reported to be related to HCV transmission. Seven SOT recipients had viral relapse, with all seven patients treated successfully. Four patients developed fibrosing cholestatic hepatitis with complete resolution post‐treatment. Conclusions Transplanting viraemic organs into uninfected individuals can become the standard of care for patients who do not have contraindications to DAAs.

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New drugs for hepatitis C virus

Cited by 5 publications

References 34 publications

A Cell-Based Assay for RNA Synthesis by the HCV Polymerase Reveals New Insights on Mechanism of Polymerase Inhibitors and Modulation by NS5A

A Cell-Based Assay for RNA Synthesis by the HCV Polymerase Reveals New Insights on Mechanism of Polymerase Inhibitors and Modulation by NS5A

2′-Deoxy-2′-spirocyclopropylcytidine Revisited: A New and Selective Inhibitor of the Hepatitis C Virus NS5B Polymerase

Systematic review: hepatitis C viraemic allografts to hepatitis C‐negative recipients in solid organ transplantation

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